Table 2.
Characteristics of studies researching macrophage-targeting drugs for OA treatment.
| First Author, Year | Study Type | Country | Population | Experimental environment | Interference |
|---|---|---|---|---|---|
| Drugs targeting macrophage-derived inflammatory cytokines | |||||
| IL-1 antagonist | |||||
| Pelletier JP, 1997 54 | Animal study | Canada | 17 dogs | In vivo + in vitro | Surgery induced knee OA + intra-articular injection of autologous cells transduced with the IL-1Ra gene |
| Caron JP, 1996 55 | Animal study | Canada | 16 dogs | In vivo | Surgery induced knee OA + intra-articular injection of recombinant human IL-1Ra |
| Chevalier X, 2009 56 | RCT | USA | 170 knee OA patients | In vivo | Anakinra (an IL-1Ra) intra-articular injection |
| Cohen SB, 2011 57 | RCT | USA | 228 knee OA patients | In vivo | AMG 108 (a fully human monoclonal antibody to IL-1R) subcutaneously or intravenously injection |
| TNF blockade | |||||
| Grunke M, 2006 58 | Case report | Germany | a 68 year old male knee OA patient | In vivo | Adalimumab (human TNF antibody) subcutaneously injection |
| Magnano MD, 2007 59 | Pilot trial | USA | 12 hands OA patients | In vivo | Adalimumab intra-articular injection |
| Fioravanti A, 2009 60 | Pilot trial | Italy | 10 hands OA patients | In vivo | Infliximab (TNF-α antagonist) intra-articular injections |
| Chevalier X, 2015 61 | RCT | France | 99 hands OA patients | In vivo | Adalimumab subcutaneous injections |
| Aitken D, 2018 62 | RCT | Australia | 51 hands OA patients | In vivo | Adalimumab subcutaneous injections every other week |
| Drugs inducing M2 polarization | |||||
| Dai M, 2018 63 | Animal study | China | Rats | In vivo + in vitro | Surgery-induced knee OA+ SCII intra-articular injections |
| Shu CC, 2020 64 | Animal study | Australia | Mice | In vivo | Surgery induced knee OA+ intra-articular injection of Hymovis (a hyaluronan hexadecylamide derivative) |
| Manferdini C, 2017 65 | In vitro test | Italy | 12 human OA synovial tissues | In vitro | M1 macrophages from OA tissues were co-cultured with ASC |
| Cherian JJ, 2015 66 | RCT | USA | 102 knee OA patients | In vivo | GEC-TGF-β1 intra-articular injection |
| Ha CW, 2015 67 | RCT | South Korea | 27 knee OA patients | In vivo | GEC-TGF-β1 intra-articular injection (high dose) |
| Cho JJ, 2017 68 | RCT | South Korea | 27 knee OA patients | In vivo | GEC-TGF-β1 intra-articular injection (high dose) |
| Cho J, 2016 69 | RCT | South Korea | 156 knee OA patients | In vivo | Invossa™ intra-articular injection |
| Lee H; 2018 70 | Animal study | South Korea | Rats | In vivo | Surgery-induced knee OA+ Invossa™ intra-articular injection |
| Drugs inhibiting M1 polarization | |||||
| Wang H, 2021 71 | Animal study | China | Mice | In vivo | Collagenase-induced OA+ Frugoside intra-articular injection |
| First Author, Year | Drug Name | Outcome | Result | Mechanism |
|---|---|---|---|---|
| Drugs targeting macrophage-derived inflammatory cytokines | ||||
| IL-1 antagonist | ||||
| Pelletier JP, 1997 54 | Autologous cells transduced with the IL-1Ra gene | Macroscopic and microscopic changes | IL-1Ra suppressed early experimental osteoarthritis | Block IL-1 receptor |
| Caron JP, 1996 55 | Recombinant human IL-1Ra | Macroscopic and microscopic changes; RNA expression | IL-1Ra suppressed experimental osteoarthritis | Block IL-1 receptor |
| Chevalier X, 2009 56 | Anakinra | WOMAC score; Adverse events | Anakinra didn’t improve joint pain and function | Block IL-1 receptor |
| Cohen SB, 2011 57 | AMG 108 | WOMAC score; Adverse events | AMG 108 didn’t improve joint pain and function | Block IL-1 receptor |
| TNF blockade | ||||
| Grunke M, 2006 54 | Adalimumab | Self-reported joint function and pain; MRI | Adalimumab improved joint function and pain | Bind with TNF |
| Magnano MD, 2007 59 | Adalimumab | ACR response; Adverse events | Adalimumab leaded to pain relief and radiographic alleviation | Bind with TNF |
| Fioravanti A, 2009 60 | Infliximab | Radiographs changes; VAS pain score | Infliximab leaded to pain relief and radiographic alleviation | Bind with TNF |
| Chevalier X, 2015 61 | Adalimumab | Number of people with 50% of VAS improvement; | Adalimumab didn’t improve joint pain and function | Bind with TNF |
| Aitken D, 2018 62 | Adalimumab | VAS pain score; AUSCAN pain score; MRI | Adalimumab didn’t improve joint pain and function | Bind with TNF |
| Drugs inducing M2 polarization | ||||
| Dai M, 2018 63 | SCII | Macroscopic and microscopic changes; RNA expression | SCII significantly improved the structural integrity of the cartilage tissue in OA rats | SCII increases M2-polariation of macrophages; SCII inhibites chondrocyte apoptosis |
| Shu CC, 2020 64 | Hymovis | Macroscopic and microscopic changes; RNA expression | Hymovis reduces allodynia at an early but not late stage of OA | Hymovis increased M2- macrophages. |
| Manferdini C, 2017 65 | ASC | Microscopic changes; RNA expression | M1-like macrophage markers downregulated while M2-like macrophage markers upregulated when cultured with ASC | ASC activates M2-macrophages while inhibits M1-macrophages |
| Cherian JJ, 2015 66 | GEC-TGF-β1 | IKDC score; VAS pain; Adverse events | GEC-TGF-β1 patients had improved scores | TGF-β induces osteogenesis and chondrogenesis; TGF-β increase M2 polarization |
| Ha CW, 2015 67 | GEC-TGF-β1 | IKDC score; WOMAC score; VAS pain; |
GEC-TGF-β1 patients had improved scores | TGF-β induces osteogenesis and chondrogenesis; TGF-β increase M2 polarization |
| Cho JJ, 2017 68 | GEC-TGF-β1 | MRI | GEC-TGF-β1 patients had improved MRI assessment parameters | TGF-β induces osteogenesis and chondrogenesis; TGF-β increase M2 polarization |
| Cho J, 2016 69 | Invossa™ | IKDC score; WOMAC score; VAS pain; KOOS score |
Invossa™ patients had improved scores | TGF-β induces osteogenesis and chondrogenesis; TGF-β increase M2 polarization |
| Lee H; 2018 70 | Invossa™ | Pain behavior; Histological staining; RNA expression |
Invossa™ rats showed pain relief, cartilage regeneration. It encouraged M2 polarization and inhibit M1 polarization | TGF-β induces osteogenesis and chondrogenesis; TGF-β increase M2 polarization |
| Drugs inhibiting M1 polarization | ||||
| Wang H, 2021 71 | Frugoside | Histological staining; RNA expression; Protein level; | Frugoside attenuates synovial inflammation and delays the development of OA | Frugoside inhibits macrophage M1 polarization |
RCT, randomized control trial; OA, osteoarthrosis; IL-1Ra, Interleukin-1 receptor antagonis; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; ACR, American College of Rheumatology; VAS, Visual Analogue Scale; AUSCAN, Australian/Canadian Hand OA Index; SCII, squid type II collagen; ASC, adipose mesenchymal stromal cell; GEC-TGF-β1, genetically engineered chondrocytes virally transduced with TGF-β1; IKDC, International Knee Documentation Committee; KOOS, Knee Injury and Osteoarthritis Outcome Score.